Non-alcoholic fatty liver disease (NAFLD) includes related disorders ranging from mild hepatic steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to fibrosis or liver cirrhosis (Cohen et al., Science, 2011, 332, 1519-1523). NAFLD affects nearly one-third of US adults (Schuppan et al., Liver Int., 2010, 30, 795-808) and is the most common chronic liver disease in both US children and adults (Lavine et al., JAMA, 2011, 305, 1659-68). Deposition of triglycerides in the cytoplasm of 5-10% of hepatocytes defines mild fatty liver disease. Like many burgeoning metabolic diseases, including type 2 diabetes (T2D), NAFLD associates with obesity and insulin resistance and likely reflects the liver's manifestation of metabolic syndrome (Schuppan et al., Liver Int., 2010, 30, 795-808). Indeed, 50-60% of patients with T2D have_NAFLD (Smith et al., Nat. Rev. Endocrinol., 2011, 7, 456-465). First line therapy for fatty liver disease includes weight loss, dietary changes and exercise; however, for most patients these interventions prove therapeutically insufficient and/or difficult to maintain. Currently, there is no FDA-approved small molecule treatment for NAFLD.
Despite being the most common chronic liver disease, accounting for 60-90% of abnormal liver blood tests (Day, Clin. Med., 2011, 11, 176-178), there is no widely implemented, treatment for NAFLD (“No treatment has been established” [Lavine et al., JAMA, 2011, 305, 1659-68; Sanyal, et al., N. Engl. J. Med., 2010, 362, 1675-1685]). While the molecular pathogenesis of NAFLD remains unclear (Cohen et al., Science, 2011, 332, 1519-1523), the predominant hepatic phenotype is cytoplasmic triglyceride accumulation. Although no clinically validated molecular target for treating NAFLD exists, small molecules that eliminate (“clear”) excess triglycerides from the liver may lead to novel treatments for NAFLD.